Oxymorphinans are prepared by cyclization of 1-benzl-1,2,3,4,5,6,7,8-octahydro-isoquinoline derivatives. For convenience these 1-benzl-1,2,3,4,5,6,7,8-octahydro-isoquinoline derivatives will be referred as ‘octabase’ henceforth. The aryl group may be substituted with the appropriate desired substituent required in the final morphinan molecule. In dextromethorphan, the substituent is 4-methoxy, which may also be generated by methylation later if a hydroxy substituent is used instead of the methoxy. The nitrogen atom of the octahydro-isoquinoline may be free base or substituted with alkyl or aralkyl groups. Here also, the option exists of N-methylation before cyclization or after cyclization. Hellerbach et al. have demonstrated that these substituents influence the outcome of cyclization in terms of yield and purity (Helv.Chim.Acta., 39, 1956, 429-440). When 1-(4-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline is cyclized, a mixture of levo and dextro isomers of methorphan is obtained. The isomers can be separated fairly easily by using resolving agents like tartaric acid, mandelic acid etc. However, only about 40% of the racemic mixture is recovered in usable form, the remaining material being of little value (Schnider and Gruessner, Helv. Chim. Acta., 34, 1951, 2211-2217). Some efforts were made to racemize the unwanted residual mixture with no success. Because of the rigid stereochemistry of the morphinan, it was expected not to undergo racemization. Mohacsi, E., has described methods of preparing 3-phenoxy-morphinans, which are obtained as racemic compounds. In passing, he mentions that the racemates can be resolved “to levorotatory compounds by any conventional method of optical resolution with acid resolving agents like tartaric acid, mandelic acid, camphor sulfonic acid, dibenzoyl tartaric acid, gulonic acid”. No examples for the resolution are given (U.S. Pat. No. 4,247,697).
It was also noted during the cyclization experiments that the stereochemistry of the resulting morphinan is dependent on the enantiomeric property of the octabase used. Because the morphinan structure is a fused ring system involving the chiral centres at the ring junctions, the structure is rigid and the chirality of the octabase determines the stereochemistry of the resulting morphinan. Thus the levorotatory octabase yields dextrorotatory morphinan and vice versa (Schnider et al, Helv.Chim.Acta., 37, 1954, 710-720). It is thus advantageous to use (−) octabase for cyclization to obtain (+) morphinan. This is possible only if there is an economically viable process for making the required chiral octabase, which is possible to achieve by either ways: (1) to resolve the racemic mixture of the octabase, use the right isomer in further cyclization process, recover and recycle the unwanted isomer or (2) prepare the required isomer of the octabase by a stereospecific synthesis. There are indeed numerous publications and patents targeting the latter approach, some being effective. However, the major drawback in all these processes are the expensive and sophisticated metal catalysts, ligands and reaction conditions required. Traditionally the resolution methods are simple, using easily available chiral resolving agents. The success of a resolution process depends on the efficiency of resolution step in separating the two isomers, yield and recovery of the desired isomer of high purity, recovery and recyclability of the resolving agent and the undesired isomer.
Schnider et al. (Helv. Chim. Acta., 37, 1954, 710-720) resolved racemic 1-(4-methoxybenzyl)-N-methyl octahydroisoquinoline with D-tartaric acid as tartrate and after recrystallisation converted to the required octabase. The tartrate salt of the undesired octabase remained in solution and recovered in low yield as tartrate and further work up gave the corresponding octabase in low yield. Our own efforts to resolve the octabase with L-(+) tartaric acid were entirely unsuccessful. In a later publication, Brossi and Schnider (Helv. Chim. Acta., 39, 1956, 1376-1386) reported resolution of the same racemic octabase with mandelic acid without details of yield or quality of the recovered octabase or recovery of the undesired isomer. In Table 1 below our results obtained using mandelic acid as a resolving agent as described in the above literature and with minor modifications are summarized.
TABLE 1Resolution with (−) Mandelic acidOR of input YieldOR of recovered mandelic (%)resolving agentExpt.acidSolventof saltOR of Saltfrom saltfrom MLs1−150° toEthyl37−126° to −150° to −135° to −152°acetate &−132°−152°−140°Methanol2−150° toEthyl38−120° to −150° to −135° to −152°acetate−125°−152°−140°3−150° toToluene————−152°4−150° toMethanol————−152°
The results show that only a mixture of solvents is able to resolve the octabase satisfactorily. Without ethyl acetate, and in single solvents, the salt does not seem to form. On an industrial scale, single solvents are preferred to achieve good recovery and recycle.
Hollander et al. have described resolution of racemic octabase with di-isopropylidene-1-ketogulonic acid, an intermediate in the synthesis of ascorbic acid from glucose, including recovery of the resolving agent and the undesired isomer (U.S. Pat. No. 3,682,925 and U.S. Pat. No. 3,955,227). However, no yields or method of recycling of either are given. The salt formation requires seeding, elevated temperature and long hours of agitation. The authors also have described resolution of the 3-hydroxy-N-methylmorphinan and 3-methoxy-morphinan with the same resolving agent but with no details of recovery of the resolving agent or the undesired isomer or how these are utilized later.
Wintermeyer et al. (U.S. Pat. No. 4727147) have described another method of resolving the isomers of 1-(4-methoxybenzyl)-octahydroisoquinoline by conversion to its acetate and spontaneous crystallization from a saturated solution by seeding with the required isomer. Their results show a good recovery of both the isomers as fairly optically pure products. The advantage is that no chiral resolving agent is used. However the process requires several recrystallisations to achieve satisfactory yields and purity. Another drawback is that there is no indication of how the undesired isomer is to be recycled or whether the purity of the desired isomer so obtained is adequate for further synthesis.
Gentile, A, et al. have reported the resolution of tetrahydropapaverine and related isoquinolines using several commercially available NSAIDs like (S)-ibuprofen, (S)-flurbiprofen, (S)-naproxen (IT2008MI319=WO2008EP52234). Hedberg et al. have listed (R)- and (S)-naproxen as resolving agents along with a number of other chiral organic acids for phenylpropanolamines, although no examples are given using these agents for resolution (U.S.20070270487). Only mandelic acid and its derivatives are actually reported in the resolution examples in this now abandoned application.
Thus, there is need for an efficient process for resolution of the racemic O-methyl octabase without N-substitution and recovery of both the isomers in good yield besides recovery and recycling of the resolving agent. To achieve commercial viability of the process, it is also imperative to regenerate the required isomer from the unwanted isomer so recovered.
Just as there are no reports of racemization of the undesired isomer of 3-oxymorphinans, there are also no reports of direct racemization of the undesired (+) octabase in the literature. Conversion of the recovered undesired isomer of the octabase to the required isomer before its cyclization to the required dextro-isomer of the morphinan thus involves chemical transformations. Schnider et al. (Helv. Chim. Acta., 37, 1954, 710-720) achieved a chemical transformation of the isomer partially by first oxidizing to N-oxide, reduction to hydroxylamine compound, cleaving of the isoquinoline ring and finally re-cyclization to racemic octabase. Obviously, the whole process proved cumbersome and uneconomic. Due to low recovery of the undesired isomeric octabase and the cumbersome recyclisation process, the scheme was never adopted commercially. Brossi and Schnider (Helv. Chim. Acta., 39, 1956, 1376-1386) designed a method of dehydrogenating the optically active octabases (both 4-hydroxy and 4- methoxybenzyl analogs with unsubstituted N-atom) to corresponding 5,6,7,8-tetrahydro- isoquinolines followed by quaternisation of the nitrogen atom with benzylbromide, hydrogenation of the isoquinoline ring with catalysts Raney-nickel in 1-methylnaphthalene or palladium-carbon in tetralin and finally debenzylation of the nitrogen atom resulting in racemic octabase. They also succeeded in direct reduction of the tetrahydro-isoquinoline with sodium and amyl alcohol with yields of 15 to 40%. Still, the whole process could not be commercially adopted. However, for this purpose they obtained the required octabases without N- substitution, from the hexabase, 1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydro-isoquinoline, by reduction with Raney-nickel which in its turn was obtained by cyclization of the amide precursor (Schnider and Hellerbach, Helv. Chim. Acta., 33, 1950, 1437). Thus, they have not reported direct racemization or resolution of the 0-methyl octabases without N-substitution.
Szanta Csala et al. (HU 170924) have reported a novel method of racemization of the unwanted isomer by treatment with sodium hypochlorite or N-chlorobenzenesulfonamide or t-butylhypochlorite followed by reduction with sodium borohydride or hydrogenation in the presence of catalysts like Raney-nickel or palladium-carbon. The yields reported are between 50 and 65%. According to them, the octabase undergoes N-chlorination and dehydrochlorination in the presence of base to yield a corresponding C═N bond, which is then reduced (hydrogenated) with the borohydride. In this process, it is necessary that the nitrogen atom is not substituted. Kenner (U.S. Pat. No. 4,556,712) has described a similar method of conversion of unwanted optically active 1-(alkoxybenzyl)-1,2,3,4-tetrahydro-isoquinoline to corresponding 3,4-dihydro-isoquinoline by oxidation (selective dehydrogenation) with hypohalites followed by hydrogenation with sodium borohydride or sodium hydride to corresponding racemic 1,2,3,4-tetrahydro-isoquinoline. The reported yields are about 54% at the final reduction stage. However they have not reported similar efforts with octabase analogs.
An effective resolution of the 0-methyl racemic octabase without N-substitution is an objective of the present invention. By effective resolution it is understood to mean to one skilled in the art a commercially viable recovery of the required (−) octabase, good recovery of the resolving agent fit for recycling and a good recovery of the unwanted (+) octabase such that it can be recycled suitably.
It is also an objective of the process of the present invention to demonstrate a satisfactory recycling of the unwanted (+) octabase so recovered for value addition.